Comparative effectiveness and durability of COVID‐19 vaccination against death and severe disease in an ongoing nationwide mass vaccination campaign

Abstract As national coronavirus disease 2019 (COVID‐19) mass vaccination campaigns are rolled out, monitoring real‐world Vaccine Effectiveness (VE) and its durability is essential. We aimed to estimate COVID‐19 VE against severe disease and death in the Greek population, for all vaccines currently in use. Nationwide active surveillance and vaccination registry data during January–December 2021 were used to estimate VE via quasi‐Poisson regression, adjusted for age and calendar time. Interaction terms were included to assess VE by age group, against the “delta” severe acute respiratory syndrome coronavirus 2 variant and waning of VE over time. Two doses of BNT162b2, mRNA‐1273, or ChAdOx1 nCov‐19 vaccines offered very high (>90%) VE against both intubation and death across all age groups, similar against both “delta” and previous variants, with one‐dose Ad26.COV2.S slightly lower. VE waned over time but remained >80% at 6 months, and three doses increased VE again to near 100%. Vaccination prevented an estimated 19 691 COVID‐19 deaths (95% confidence interval: 18 890–20 788) over the study period. All approved vaccines offer strong and also durable protection against COVID‐19 severe disease and death. Every effort should be made to vaccinate the population with at least two doses, to reduce the mortality and morbidity impact of the pandemic.


| INTRODUCTION
The efficacy of coronavirus disease 2019 (COVID-19) vaccines in preventing symptomatic infection has been documented in multiple clinical trials [1][2][3][4] and observational studies. 5,6 However, as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transitions towards endemicity, 7 preventing severe COVID-19 through vaccination becomes a strategic priority to reduce overall disease burden and mortality and safeguard healthcare services. Therefore monitoring COVID-19 Vaccine Effectiveness (VE) against severe disease and death in a real-life setting is essential, to quantify the benefits of vaccination, generate confidence in the public and promote uptake. Long-term 2 | MATERIALS AND METHODS

| Study population and data collection
In Greece, the National Public Health Organization (EODY) is responsible for COVID-19 surveillance, with particular emphasis on active case finding and follow-up of all severe cases nationwide. A severe COVID-19 case is defined as a laboratory-confirmed case (using PCR or antigen testing) that has been intubated and/or hospitalized in intensive care or has died (regardless of setting). As the availability of intensive care beds varied during the pandemic, we focused on intubation and death as the two most unbiased and completely ascertained outcomes. COVID-19 deaths were defined under World Health Organization guidelines as those with laboratory confirmation and clinically compatible illness without complete recovery preceding death, and with no time cut-off following laboratory confirmation. 8 For the study period between January 11, 2020 and December 8, intubations and deaths for each vaccination group, based on the dates of laboratory confirmation (rather than dates of intubation or death).
No funding was received for this study. The study was approved by the EODY board; as only anonymized data were used from which no person can be identified, no separate ethical approval was required. The board had no role in study design, analysis, interpretation of data, and decision to publish.  (Table S2). In case of severe collinearity (Variance Inflation Factor over 5) or sparse data (<5 tabulated events) the respective interaction terms were dropped from model B. Also the interaction term between vaccine and time since the last dose was dropped for 3-dose vaccination as follow-up time was too short (Table S3). Stratified VE estimates were calculated as linear combinations of the respective model coefficients. We additionally used the fitted models to estimate the number of intubations and deaths prevented by vaccination during the study period, as the predicted number of outcome events if everyone was unvaccinated, minus observed events. 9 All statistical analyses were performed with the R statistical environment, version 4.1.2.  Table 1; although a substantial number of vaccinated persons died of COVID-19, crude and age-adjusted rates were several times lower compared to the unvaccinated group. Vaccinated individuals, especially those that received three doses, were also older on average than the unvaccinated (Table 1) Adjusted VE estimates from models A and B are presented in Figures 2, S1, and S2. Two COVID-19 vaccine doses offered more than 90% protection against death and intubation across all age groups, with marginally lower protection in persons 80 years or older. VE against death was similar for both "delta" and previously circulating variants, and even slightly higher against intubation from the "delta" variant (p < 0.001). However, 2-dose VE waned slightly over time while still being over 80% at 6 months, and a third vaccine dose restored it close to 100% even in the oldest age group. Effectiveness for one vaccine dose was suboptimal but still sufficient to halve the rate of both death and intubation compared with the unvaccinated (Figure 2). COVID-19 intubations (95% CI: 6251-7241). Finally, there was a very steep age gradient in the rate of COVID-19 death, with more than a thousand-fold difference between the younger and older age groups; a similar gradient was observed for intubations but the rate was lower in people older than 80 years, suggesting clinicians may avoid invasive mechanical ventilation in severely ill elderly patients (Figure 3). 10

| DISCUSSION
Our study provides important real-world validation for the remarkable effectiveness and durability of COVID-19 vaccination against severe disease or death. VE was similar and very high (>90%) across all age groups, despite the absolute benefit being higher for older people due to their much higher susceptibility. Furthermore, effectiveness was similar against the "delta" variant of SARS-CoV-2 compared to "alpha" and older variants, as seen in other populations. 11,12 The findings confirm that vaccination is by far the most important public health tool to blunt the mortality and morbidity impact of the COVID-19 pandemic, prevent overloading of healthcare services and save lives. 13 With the large size and long follow-up of our study population, we were able to demonstrate a small, yet statistically significant, waning of effectiveness against severe disease and death. Even in the oldest age group though, VE 6 months after two doses of mRNA or ChAdOx1 nCoV-19 vaccine remained higher than 80%, a very substantial level of protection, which is restored by a third dose to levels even higher than the initial 2-dose vaccination. Our findings are very similar to a recent study from England using the test-negative design. 14 Notably though, the difference in VE between 2-dose and 3-dose vaccination is much smaller than between 1-dose and 2-dose, or 1-dose and being unvaccinated; therefore for public health authorities, closing the existing COVID-19 vaccination gaps is an even more urgent priority than offering third doses to the population. 15 While the benefit from a third dose needs to be balanced against the ethical and utilitarian need for global vaccine equity, 16 an additional challenge is presented by the "omicron" variant given the substantial effectiveness of third doses in preventing "omicron" symptomatic infection. 17 Therefore to meet global demand, vaccine manufacturers have to urgently scale up production.
The four examined vaccines showed only marginal differences in effectiveness. Interestingly, VE for 1-dose Ad26.COV2.S is consistent with its postvaccination antibody response, which is initially lower but more stable over time. 18 The similar VE for all vaccines is important, as there are no head-to-head randomized trials, and provides valuable reassurance to the public who might ask which vaccine is best. It also shifts considerations about specific vaccine recommendations away from effectiveness and primarily towards availability, logistics, and safety profile issues.